Options in Mantle Cell Lymphoma Therapy

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1 Options in Mantle Cell Lymphoma Therapy Carlo Visco, MD Dept of Cell Therapy and Hematology San Bortolo Hospital, Vicenza, taly

2 My Disclosures: ADVSOR OR ADVSORY BOARDS: Lundbeck Canada nc, Celgene Europe, Mundipharma nternational RESEARCH FUNDS: Mundipharma Pharmaceuticals taly

3 Mantle cell lymphoma (MCL) About 6% of non Hodgkin s lymphomas Predominantly elderly (>60), male patients Advanced Ann Arbor stage Extranodal involvement (bone marrow, gastrointestinal tract, liver, spleen)

4 Model of molecular pathogenesis of MCL Genetically stable t(11;14), SOX11- cells GC MZ Modified from Jares et al, JC 2012

5 Patients in whom treatment may be postponed (imcl) Long history of asymptomatic disease Non-nodal leukemic disease (++ spleen) Low proliferation rate Hypermutated GHV Noncomplex karyotypes SOX11-negative Fernandez V, Cancer Res 2010 Seto M, Blood 2013 Ferrando A, Blood 2013 Vegliante et al, Blood 2013

6 Cause-specific survival of the main B-cell lymphoma subtypes Oncology nstitute of Southern Switzerland, Ghielmini and Zucca, Blood 2009 Significant improvement in OS in the last 10 years: 1) introduction of dose-intensive strategies upfront in younger patients 2) availability of novel agents in older patients or in the r/r setting.

7 Standard 1st line in younger patients with MCL NDUCTON CHEMOTHERAPY ASCT ARA-C including R-Hyper-CVAD

8 LyMa trial MCL, 18 to 65 years old W1 W4 W7 W10 OBSERVATON R-DHAP R-DHAP R-DHAP R-DHAP R-BEAM f < VGPR R-CHOP f > VGPR RTUXMAB MANTENANCE every 2 months during 3 years Le Gouill et al. ASH 2012

9 CHOP21 CHOP21 CHOP21 HD-CTX HDAra-C HDAra-C BEAM+ ASCT +FRT Gy L MCL 0208 trial QuickTime and a GF decompressor are needed to see this picture wks R R R R R R R Len 15 mg days 1-21 every 28 days /2 yrs Observation Cortelazzo et al. ongoing

10 Elderly ( 65)/unfit patients

11 CHOP vs Rituximab-CHOP ORR (%) CR (%) R-CHOP TTF CHOP 75 7 Median age 61 (1/3>65) No difference in DOR or OS* Lenz et al, JCO 2005

12 60 years : is Flu-regimen better than CHOP? : does maintenance with Rituximab prolong remission?

13 R-CHOP vs R-FC in elderly patients with MCL ORR (%) CR (%) R-CHOP R-FC Cause of death R-FC R-CHOP Died in CR/PR 10% 4% nfections 7% 4% Second cancer 3% 1% Kluin-Nelemans HC et al. NEJM 2012;367:520-31

14 Maintenance therapy: Rituximab vs nterferon α Remission Duration, Patients assigned to R-FC Overall Survival, Patients assigned to R-FC Kluin-Nelemans HC et al. NEJM 2012;367:520-31

15 Median age of the MCL pts 70 years (65-74) Rummel MJ et al. Lancet 2013;381:

16 Bendamustine plus Rituximab (BR) vs R-CHOP/CVP BRGHT study 447 patients with indolent NHL or MCL randomized to 6-8 cycles of BR or R-CHOP/R-CVP Complete Response Rate Population, Analysis BR % R-CHOP/ R-CVP % Ratio (95% C) P value Randomized MCL ( ) Flinn W et al. Blood 2014;123:

17 B-R + Observation vs B-R + 2 years Rituximab Maintenance NHL MANTAN Waldenström s Marginal zone R Mantle cell (for patients not eligible for APBSCT) Bendamustine-Rituximab + Observation Bendamustine-Rituximab + 2 years Rituximab q2 mo Rummel et al, ASH 2012 [Abstr 2739

18 Bendamustine including combinations Ongoing studies in elderly MCL Study Phase Treatment BERT (University Mainz) LENA-BERT (NLG-MCL4 Trial) R2-B (FL) R-BAC500 (FL) RBVD (GOELAMS) / Temsirolimus plus bendamustine and rituximab for patients with FL or MCL in first to third relapse Lenalidomide, bendamustine and rituximab as first-line therapy for patients over 65 years with MCL Lenalidomide, bendamustine and rituximab as a second-line therapy for 1st relapsed-refractory MCL Age-adjusted rituximab, bendamustine, cytarabine as induction therapy in older patients with MCL Study of MCL treatment by Rituximab, Velcade, Bendamustine and Dexamethasone (1 st -line) Primary completion date Mar 2015 Sep 2014 Jul 2014 Mar 2014 Apr 2015 Ohio State University Rituxan/Bendamustine/PC in Relapsed DLBCL, MCL, or ndolent Non-Hodgkin's Lymphoma Oct 2015 North American ntergroup Trial Rituximab, bendamustine ± Velcade ± R2 maintenance as 1st line therapy for elderly MCL patients Apr 2015

19 E1411 North American ntergroup Trial NCT

20 and Mechanism of action Alkylator group Benzimidazole ring bendamustine JEKO-1 GRANTA-519 S-phase Visco et al, BCMD 2012 Hiraoka, et al, PLOS 2014

21 Rituximab, Bendamustine, Cytarabine (R-BAC) ORR (%) CR (%) Untreated Median age 71 (54-82) Median F/U 48 months (28-63) R/R Visco C et al, JCO ,8,6,8,6 37 months,4 Previously untreated (n=20),4,2 0,2 0 Relapsed/Refractory (n=20) Months Time Visco C et al. Unpublished data

22 PFS Elderly MCL-Provocative comparison Upfront Relapsed/Refractory 1 R-BAC, nr R-Benda 35 months 1 R-BAC 37 months R-Benda months,8,8,6,6,4,4,2 0 R-CHOP ± R maint months,2 0 R-Lena, brutinib, R-FCM months Time (months) Time (months)

23 Phase 2 study of age-adjusted R-BAC (RBAC500) Two stages, phase 2 study ntroduction of MRD and CGA assessment Ara-C dose reduction to 500 mg/m 2 Previously untreated >65 years or unfit 57 patient enrolled [2 May Feb 2014] Expected 1 st report Lugano 2015

24 Active «biologic» agents Proteasome nhibitors [Bortezomib] 1st drug approved in the USA for MCL M-TOR inhibitors [Temsirolimus] 1st drug approved in the EU for MCL B-cell receptor downstream pathways inhibitors [brutinib, delalisib] mmunomodulators [Lenalidomide]

25 Lenalidomide + Rituximab for relapsed or refractory MCL: a phase / trial DOR 19 months 44 patients, median age 66 (46-85) Phase 1: MTD 20 mg Phase 2: ORR 57%, CR 36% PFS 11.1 months Wang, Lancet Oncol 2012

26 Chemo-free approach Combination Biologic Therapy Without Chemotherapy As nitial Treatment For Mantle Cell Lymphoma: Multi-Center Phase Study Of Lenalidomide Plus Rituximab nduction phase (Lena 20 mg) + maintenance phase (Lena 15 mg) 31 subjects with previously untreated MCL, median age 65 years (range 42-86) Median follow-up 12 months (range 5-23 months) ORR 77% with 40% CR/CRu Median time to objective response was 2.8 months 87% remain on study without evidence of progression Martin P, ASH 2013

27 brutinib, a Bruton tyrosine kinase inhibitor Phase 2 study Open-label, multicenter international study (18 sites) 68% 67% 68% CR PR Patients with R/R MCL (N = 115) Median 3 prior therapies Patients received a daily dose of ibrutinib until disease progression or unacceptable levels of adverse events (AEs) Patients (%) 19% 49% 23% 44% 21% 47% Wang ML, NEJM 2013

28 brutinib Efficacy: PFS 13.9 months Wang ML, NEJM 2013

29 NLG-MCL6 (PHLEMON) brutinib+lenalidomide+rituximab Phase study in R/R MCL R R R R R R R R R R R R CT CT, PET CT, PET MRD MRD L L L L L L L L L L L L Weeks Weeks Maintenance until progression Courtesy of M Jerkemann

30 Conclusions ntensified protocols containing Ara-C ensure prolonged remissions in younger/fit patients For them, the role of maintenance and of autotransplant still debated (results soon) R-CHOP + R maintenance standard therapy for many groups in the elderly/unfit R-Benda is significantly challenging R-CHOP A list of biologic agents that target tumor cells and microenvironment Many low-toxic associations emerging Chemo-free approaches next step

31 Thank you! Enjoy Toronto and CHC 2014